Imaging second messenger dynamics in developing neural circuits

Dunn, Timothy A.; Feller, Marla B.

doi:10.1002/dneu.20619

Cited by 24 publications

(17 citation statements)

References 87 publications

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“…The D 1 responses in the cerebral cortex reported here are clearly consistent with these previous findings, suggesting that cAMP concentrations in the sub‐micromolar range and partial PKA activation in response to neuromodulatory stimulation are common features of various mature neurones in brain slice preparations. This observation contrasts strongly with the strong (micromolar) spontaneous or stimulated cAMP signals reported by Epac sensors in cultured embryonic neurones (Gorbunova & Spitzer, 2002; Nikolaev et al 2004; Dunn et al 2006; Dunn & Feller, 2008; Calebiro et al 2009; Shelly et al 2010; Nicol et al 2011). These large cAMP oscillations or strong responses to neuromodulators in embryonic neurones might be a normal feature of growth, path‐finding and maturation processes, whereas mature neurones need to maintain tight control over cAMP concentration, possibly to ensure spatial compartmentation of the cAMP signal.…”

Section: Discussioncontrasting

confidence: 83%

Striatal neurones have a specific ability to respond to phasic dopamine release

Castro¹,

Brito²,

Guiot³

et al. 2013

The Journal of Physiology

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Key points• Dopamine D 1 receptors activate the cAMP/protein kinase A (PKA) pathway in both cortex and striatum, with different types of signalling enzymes being involved in cAMP/PKA signal integration. We investigated the functional implications of such differences.• Biosensor imaging in mouse brain slice preparations revealed that the cAMP/PKA signal increases faster, reaches higher levels and lasts longer in striatal neurones than in cortical neurones.• These differences result from faster cAMP production and lower degradation by type 4 phosphodiesterase activities in the striatum than in the cortex. In addition, DARPP-32 in the striatum prolongs the PKA response by inhibiting phosphatases.• These molecular features confers on striatal neurones a particular ability to temporally decode sub-second dopamine signals associated with reward and learning.Abstract The cAMP/protein kinase A (PKA) signalling cascade is ubiquitous, and each step in this cascade involves enzymes that are expressed in multiple isoforms. We investigated the effects of this diversity on the integration of the pathway in the target cell by comparing prefrontal cortical neurones with striatal neurones which express a very specific set of signalling proteins. The prefrontal cortex and striatum both receive dopaminergic inputs and we analysed the dynamics of the cAMP/PKA signal triggered by dopamine D 1 receptors in these two brain structures. Biosensor imaging in mouse brain slice preparations showed profound differences in the D 1 response between pyramidal cortical neurones and striatal medium spiny neurones: the cAMP/PKA response was much stronger, faster and longer lasting in striatal neurones than in pyramidal cortical neurones. We identified three molecular determinants underlying these differences: different activities of phosphodiesterases, particularly those of type 4, which strongly damp the cAMP signal in the cortex but not in the striatum; stronger adenylyl cyclase activity in the striatum, generating responses with a faster onset than in the cortex; and DARPP-32, a phosphatase inhibitor which prolongs PKA action in the striatum. Striatal neurones were also highly responsive in terms of gene expression since a single sub-second dopamine stimulation is sufficient to trigger c-Fos expression in the striatum, but not in the cortex. Our data show how L. R. V. Castro and M. Brito contributed equally to this work and are joint first authors.

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Section: Discussioncontrasting

confidence: 83%

Striatal neurones have a specific ability to respond to phasic dopamine release

Castro¹,

Brito²,

Guiot³

et al. 2013

The Journal of Physiology

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“…Thus, careful analysis of intracellular cAMP levels is mandatory in any experimental application of PAC transgenes, and various analytical techniques are available, e.g. immunodetection by ELISA, electrophysiological quantification, or use of FRET-based imaging techniques (7,26,27).…”

Section: Discussionmentioning

confidence: 99%

Light Modulation of Cellular cAMP by a Small Bacterial Photoactivated Adenylyl Cyclase, bPAC, of the Soil Bacterium Beggiatoa

Stierl

Stumpf

Udwari

et al. 2011

Journal of Biological Chemistry

364

423

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The recent success of channelrhodopsin in optogenetics has also caused increasing interest in enzymes that are directly activated by light. We have identified in the genome of the bacterium Beggiatoa a DNA sequence encoding an adenylyl cyclase directly linked to a BLUF (blue light receptor using FAD) type light sensor domain. In Escherichia coli and Xenopus oocytes, this photoactivated adenylyl cyclase (bPAC) showed cyclase activity that is low in darkness but increased 300-fold in the light. This enzymatic activity decays thermally within 20 s in parallel with the red-shifted BLUF photointermediate. bPAC is well expressed in pyramidal neurons and, in combination with cyclic nucleotide gated channels, causes efficient light-induced depolarization. In the Drosophila central nervous system, bPAC mediates light-dependent cAMP increase and behavioral changes in freely moving animals. bPAC seems a perfect optogenetic tool for light modulation of cAMP in neuronal cells and tissues and for studying cAMP-dependent processes in live animals.

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“…Such antidepressant inhibition of [Ca 2+ ] i may be attributed to antidepressant-induced activation of the cAMP/PKA pathway and vice versa, since calcium and cAMP pathways are known to be closely interrelated [65]. However, antidepressant inhibition of [Ca 2+ ] i may be sufficient to exert anti-neuroinflammatory effects, since chelating intracellular calcium has been demonstrated to reduce NF-B activity and generation of IL-6 and MCP-1 in murine astrocytes exposed to the human immunodeficiency virus protein Tat [66].…”

Section: Possible Mechanisms Of Anti-inflam-matory Effects Of Antidepmentioning

confidence: 99%

Antidepressants and Neuroinflammation: Can Antidepressants Calm Glial Rage Down?

Hashioka

2011

MRMC

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Neuroinflammation is traditionally defined as the brain's innate immune response and is also considered to be a glial-cell propagated inflammation. Increasing evidence indicates that neuroinflammation plays an important role in some cases of major depression and also that antidepressants possess anti-neuroinflammatory properties. Inhibition of neuroinflammation may represent a novel mechanism of action of antidepressant treatment. In vivo studies with animal models of neurological conditions have shown that various types of antidepressants exert inhibitory effects on the expression of inflammatory mediators, including cytokines, as well as on both microgliosis and astrogliosis in the inflamed CNS. In vitro studies using pathologically activated rodent microglia or mixed glial cells have demonstrated that various types of antidepressants diminish glial generation of inflammatory molecules. One of the most plausible mechanisms of such anti-neuroinflammatory efficacy of the drugs, as well as their antidepressant actions, seems to involve elevated intracellular cAMP levels. But the exact mechanism has still to be elucidated.

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Imaging second messenger dynamics in developing neural circuits

Cited by 24 publications

References 87 publications

Striatal neurones have a specific ability to respond to phasic dopamine release

Striatal neurones have a specific ability to respond to phasic dopamine release

Light Modulation of Cellular cAMP by a Small Bacterial Photoactivated Adenylyl Cyclase, bPAC, of the Soil Bacterium Beggiatoa

Antidepressants and Neuroinflammation: Can Antidepressants Calm Glial Rage Down?

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